For decades, medicaments have been packaged in vials, ampoules, cartridges or syringes made of glass. The combination of different material properties of glass, in particular the high transparency, the mechanical resistance, the low penetrability and permeability in combination with the high chemical resistance, is critical for maintaining the quality of the medicaments and thus the efficacy thereof.
Despite this general suitability of glass materials, various properties of a medicament (e.g. ionic strength, pH, composition of a buffer present) can, under certain fabrication and storage conditions, lead to chemical reactions even with highly-resistant glasses, such as borosilicate glasses. A possible consequence of such reactions is corrosion processes in which particles in lamellae or leaflet form are formed, which can detach from the glass wall still during the storage period. This behavior of glass is also termed “delamination”, owing to the detachment of the particles from the glass wall.
The expression “delamination”, which customarily denotes the detachment of layers in compound materials, or the detachment of a corrosion layer on a steel component, was applied to the glass sector for this phenomenon.
The delamination of glass originates from interactions of chemical compounds with the glass surface which are highly complex and are not completely understood. Basically, the process proceeds via 2 mechanisms: the first mechanism is extraction of components from the surface of the glass by a diffusion-controlled ion-exchange process. The second mechanism is the alkaline attack which is also termed hydrolysis or network attack which proceeds in addition to and simultaneously to the first, and effects the dissolution of the glass surface and thereby the release of the components of the glass matrix. Both mechanisms contribute to the delamination of glass; an increase, e.g., in ionic strength, elevation of the pH, increase in the surface to volume ratio, and also thermal processing can amplify the delamination.
The glass composition likewise plays a role in these mechanisms. If glasses have high contents of poorly soluble components, such as, for example, silicon dioxide, aluminum oxide, titanium dioxide and/or oxides of the rare earths, virtually no extraction from the glass matrix is observed, and also no local corrosion occurs. Other components, such as alkali metal oxides and alkaline earth metal oxides, and also the network formation agents boron oxide and phosphorus oxide can in contrast be extracted more readily from the glass matrix.
The extent of delamination depends, as well as on the type and composition of the medicament formulation, and the glass composition, also to a great extent on the selected fabrication process for the glass packaging, such as vials, ampoules, cartridges, syringes and the like. For example, vials formed from a glass tube only exhibit delamination, with formation of the described lamellae, within the wall region that is greatly heated in the reshaping.
In 2009, 2010 and 2011, a great number of medicament batches had to be recalled from the market because of delamination of the glass packaging means that occurred, wherein the most varied products and companies were affected. In addition to the great financial loss and damage to the reputation which such a recall causes, in particular protection of the patient demands avoidance of such damaged packaging material.
As already described, the delamination forms first in the course of storage, and thus cannot be observed by an inspection immediately after charging the medicaments into the corresponding glass packaging means and thereby avoided. In order, nevertheless, to make a prediction on the risk of damaged packaging occurring in a predictable time, for example, accelerated aging tests are used in which the packaged medicament or individual components of the medicament (e.g. placebo solution without active ingredient) are stored, for example at an elevated temperature (30° C. to 60° C.). After an interval of several days, weeks or months, a visual inspection is then made with respect to the characteristic lamellae.
Similar tests are also carried out with buffers usual in pharmacy, such as citrate, phosphate and the like, or with certain test substances, such as solutions containing glutaric acid or glycine.
The known pharmaceutical analyses of glass delamination are therefore concerned principally with the effect of delamination on the medicament quality and are based on studies of the drug present per se, the changes of the properties and efficacy thereof, the purity thereof and the like, i.e. the tests study the changes of the medicament owing to the contact with the inner wall of the glass vessel with the medicament. Such methods are described, for example, in Iacocca, R. G., Toltl, N., et al., Factors Affecting the Chemical Durability of Glass Used in the Pharmaceutical Industry, AAPS PharmSciTech, Aug. 26, 2010; DOI: 10.1208/s12249-010-9506-9; Ennis R D, Pritchard R, et al., Glass vials for small volume parenterals: influence of drug and manufacturing process on glass delamination, Pharm. Dev. and Tech., 2001, 6(3):393-405. Customarily, the tests described in the literature extend over some weeks or a few months.
However, the abovementioned accelerated aging tests have serious disadvantages:
The evaluation proceeds exclusively on the basis of an optical inspection with respect to the presence of lamellae in the medicament. Detachment of the lamellae from the glass wall, however, occurs more or less by chance and can be promoted by mechanical forces, such as by shaking or other external manipulations, for instance. Against this background, only great differences in the delamination tendency may be demonstrated.
In addition, differing compositions of the medicaments have a differing effect on the glass packaging selected, in such a manner that a general statement on glass delamination of the containers cannot be made, but only specific individual cases are ever studied.
Finally, the accelerated aging tests require too much time and are too specific in order to use them in-line during manufacture of the glass packaging means. For this purpose, a test is required which delivers a test result in a relatively short time, that is to say within one day for instance, and thus permits control of the manufacture.
The object of the present invention is therefore to avoid the above-described disadvantages of the prior art and to provide a test method which, in a relatively short time span, and reliably, permits evaluation of the delamination tendency of glass packaging means. The test method should be able to be carried out even before packaging of a medicament into a glass packaging means, in such a manner that the use of damaged or unsuitable packaging material can as far as possible be excluded. The test method should be usable even during manufacture of the glass packaging material or glass packaging means, in order in this manner to be able to perform modifications and/or adaptations of the glass material or the glass packaging means still during the manufacturing process.